PROJECT SUMMARY Visceral pain is among the most frequent type of pain experienced by patients with advanced cancer. This is largely mediated by elevated levels of inflammation. Opioid-derived drugs remain the preferred prescribed analgesic for cancer-induced pain despite their induction of gut dysbiosis, tolerance, liver and kidney toxicity, and opioid-induced hyperalgesia. For these reasons it is imperative to identify complementary therapies to treat visceral pain. Ojeok-san is an oriental herbal formula, commonly used in Asian countries for its anti- inflammatory, immunoregulatory, and analgesic properties. However, its effects on cancer-induced visceral pain have not yet been examined. The long-term goal is to develop the herbal formula Ojeok-san as a clinically testable dietary regimen to delay and/or prevent cancer-induced visceral pain. The short-term goal is to determine the benefits and mechanisms of action of Ojeok-san in a preclinical model of cancer-induced visceral pain. The central hypothesis is that Ojeok-san attenuates cancer induced visceral pain by polarizing macrophages to an anti-inflammatory phenotype and decreasing TNF?. This hypothesis will be tested in three related, but independent aims. Specific Aim 1 will assess the benefits of Ojeok-san on cancer-induced visceral pain; Specific Aim 2 will determine whether Ojeok-san influences macrophage polarization and interaction with sensory neurons in cancer-induced visceral pain; and Specific Aim 3 will examine whether the analgesic effects of Ojeok-san in cancer induced visceral pain are mediated through the cytokine TNF?. Collectively, the proposed studies will elucidate the mechanism of action of Ojeok-san on cancer-induced visceral pain. Understanding the mechanism by which an herbal formula, such as Ojeok-san, can serve as an analgesic is of critical importance to the development of novel treatments dedicated to alleviate visceral pain. The research- training plan in this K99/R00 proposal includes multifaceted guidance and mentoring on complementary and integrative health, immunology, and neuroscience. Taken together, the training plan, the Mentors, the Consultants, the External Advisory Committee, the enriched environment at the University of South Carolina including the Center for Complementary and Alternative Medicine, Center of Dietary Supplements and Inflammation, and the Center for Colon Cancer Research, will be fundamental for my successful transition to an independent scientist in the field of complementary medicine in cancer pain.